Preclinical study reveals that USP14 stabilizes MTDH to drive metastasis and chemoresistance in head and neck cancer, highlighting USP14 inhibition as a potential therapeutic strategy.
Key Points
To elucidate the regulatory mechanisms driving MTDH stabilization and determine its role in head and neck squamous cell carcinoma metastasis and chemoresistance.
Characterized the competitive binding interactions among USP14, the ubiquitin ligase FBXW7, and MTDH using biochemical and functional assays.
Evaluated downstream NF-κB activation, epithelial-mesenchymal transition, and cancer stem cell phenotypes after USP14 inhibition and MTDH rescue.
Analyzed clinical metastatic head and neck squamous cell carcinoma tissues to determine USP14 and MTDH expression levels and correlation.
USP14 functioned as a deubiquitinase that competitively hindered FBXW7-mediated degradation of MTDH, maintaining MTDH stability.
Stabilized MTDH triggered NF-κB signaling, promoting epithelial-mesenchymal transition, cancer stem cell maintenance, metastasis, and drug resistance.
Inhibition of USP14 suppressed aggressive tumor phenotypes in an MTDH-dependent manner, aligning with elevated co-expression of USP14 and MTDH in metastatic clinical tissues.